Draft Genome Sequence of Bifidobacterium adolescentis 4-2, Isolated from Healthy Human Feces

Bifidobacterium adolescentis 4-2 was isolated from healthy human feces. Here, we report a draft genome sequence of this bacterium, which may clarify the functionality of gut microbiota-brain communication. The draft genome comprises 2.39 Mb, with an average G+C content of 59.2% and 2,028 coding DNA sequences. An operon for GABA biosynthesis was observed in the draft genome.

Bifidobacterium bifidum Shows More Diversified Ways of Relieving Non-Alcoholic Fatty Liver Compared with Bifidobacterium adolescentis

The occurrence of non-alcoholic fatty liver disease (NAFLD) is closely related to intestinal microbiota disturbance, and probiotics has become a new strategy to assist in alleviating NAFLD. In order to investigate the effect of Bifidobacterium on NAFLD and the possible pathway, a NAFLD model was established by using a high-fat diet (HFD) for 18 weeks. Fourteen strains of Bifidobacterium were selected (seven Bifidobacterium adolescentis and seven Bifidobacterium bifidum) for intervention. The effects of different bifidobacteria on NAFLD were evaluated from liver cell injury, liver fat deposition, liver inflammatory state and liver histopathology, and were taken as entry points to explore the mitigation approaches of bifidobacteria through energy intake, lipid metabolism, glucose metabolism and intestinal permeability. The results showed that Bifidobacterium exerts species-specific effects on NAFLD. B. bifidum exerted these effects mainly through regulating the intestinal microbiota, increasing the relative abundance of Faecalibaculum and Lactobacillus, decreasing the relative abundance of Tyzzerella, Escherichia-Shigella, Intestinimonas, Osillibacter and Ruminiclostridium, and further increasing the contents of propionic acid and butyric acid, regulating lipid metabolism and intestinal permeability, and ultimately inhibiting liver inflammation and fat accumulation to alleviate NAFLD. B. adolescentis exerted its effects mainly through changing the intestinal microbiota, increasing the content of propionic acid, regulating lipid metabolism and ultimately inhibiting liver inflammation to alleviate NAFLD.

Bifidobacterium adolescentis Alleviates Liver Steatosis and Steatohepatitis by Increasing Fibroblast Growth Factor 21 Sensitivity

The gut microbiota is a newly identified contributor to the development of non-alcoholic fatty liver disease (NAFLD). Previous studies of Bifidobacterium adolescentis (B. adolescentis), a species of Bifidobacterium that is common in the human intestinal tract, have demonstrated that it can alleviate liver steatosis and steatohepatitis. Fibroblast growth factor 21 (FGF21) has long been considered as a biomarker of NAFLD, and recent studies have shown the protective effect of FGF21 analogs on NAFLD. We wondered whether B. adolescentis treatment would alleviate NAFLD via the interaction with FGF21. To this end, male C57BL/6J mice on a choline-deficient high-fat diet (CDHFD) were treated with drinking water supplemented with B. adolescentis for 8 weeks, followed by the acute administration of recombinant mouse FGF21 protein (rmFGF21) to conduct the FGF21 response test. Consistent with previous studies, B. adolescentis supplementation reversed the CDHFD-induced liver steatosis and steatohepatitis. This was evaluated on the NAFLD activity score (NAS), reduced liver enzymes, and lipid accumulation. Further studies demonstrated that B. adolescentis supplementation preserved the gut barrier, reduced the gut microbiota-derived lipopolysaccharide (LPS), and inhibited the hepatic TLR4/NF-κB pathway. This was accompanied by the elevated expressions of the receptors of FGF21, fibroblast growth factor receptor 1 (FGFR1) and β-klotho (KLB), in the liver and the decreased expression of FGF21. The results of FGF21 response test showed that B. adolescentis supplementation alleviated the CDHFD-induced FGF21 resistance. In vivo experiments suggested that LPS could suppress the expression of FGF21 and KLB in a dose-dependent manner. Collectively, this study showed that B. adolescentis supplementation could alleviate NAFLD by increasing FGF21 sensitivity.

Human gut bifidobacteria inhibit the growth of the opportunistic fungal pathogen Candida albicans

The human gut microbiota protects the host from invading pathogens and the overgrowth of indigenous opportunistic species via mechanisms such as competition for nutrients and by production of antimicrobial compounds. Here, we investigated the antagonist activity of human gut bacteria towards Candida albicans, an opportunistic fungal pathogen that can cause severe infections and mortality in susceptible patients. Co-culture batch incubations of C. albicans in the presence of faecal microbiota from six different healthy individuals revealed varying levels of inhibitory activity against C. albicans. 16S rRNA gene sequence profiling of these faecal co-culture bacterial communities showed that the Bifidobacteriaceae family, and Bifidobacterium adolescentis in particular, were most correlated with antagonistic activity against C. albicans. Follow up mechanistic studies confirmed that culture supernatants of Bifidobacterium species, particularly B. adolescentis, inhibited C. albicans in vitro under both aerobic and anaerobic conditions. Production of the fermentation acids acetate and lactate, together with the concomitant decrease in pH, were strong drivers of the inhibitory activity. Bifidobacteria may therefore represent attractive targets for the development of probiotics and prebiotic interventions tailored to enhance inhibitory activity against C. albicans in vivo.

Effects of Bacteroides-Based Microecologics against Antibiotic-Associated Diarrhea in Mice

Antibiotic-associated diarrhea (AAD) is a self-limiting disease mediated by antibiotic therapy. In clinical practice, several types of probiotics are used in treating AAD, but minimal research has been done on Bacteroides-based microecologics. Our aim was to evaluate the therapeutic effects of Bacteroidetes uniformis FGDLZ48B1, B. intestinalis FJSWX61K18, Bifidobacterium adolescentis FHNFQ48M5, and B. bifidum FGZ30MM3 and their mixture on AAD in mice. The lincomycin hydrochloride-induced AAD models were gavaged with a single strain or a probiotic mixture for a short period to assess the changes in colonic histopathology and cytokine concentrations, intestinal epithelial permeability and integrity, short-chain fatty acids (SCFAs), and the diversity of intestinal microbiota. Our data indicated that both the sole use of Bacteroides and the combination of Bacteroides and Bifidobacterium beneficially weakened systemic inflammation, increased the recovery rate of tissue structures, increased the concentrations of SCFAs, and restored the gut microbiota. Moreover, the probiotic mixture was more effective than the single strain. Specifically, B. uniformis FGDLZ48B1 combined with the B. adolescentis FHNFQ48M5 group was more effective in alleviating the pathological features of the colon, downregulating the concentrations of interleukin (IL)-6, and upregulating the expression of occludin. In summary, our research suggests that administration of a mixture of B. uniformis FGDLZ48B1 and B. adolescentis FHNFQ48M5 is an effective approach for treating AAD.

Mycobiome Supporting Diet to Reduce Gastrointestinal (GI)Toxicity Associated with Autologous Stem Cell Transplant (ASCT) for Patients with Multiple Myeloma (MM)

Emerging data suggest healthy microbiome helps to protect against mucosal injury and inflammation. Dysbiosis results in biofilm formation in the gut which has been shown to be pro-inflammatory. MM patients potentially have significant dysbiosis result of long term corticosteroid use. Our group, previously showed that composition of microbiome presents at the pre-transplant period correlates with rate and degree of post-ASCT GI toxicities, neutropenic fever and neutrophilic engraftment among MM patients. Also, our data suggested a link between microbial communities at the count nadir and GI toxicity after high dose melphalan and ASCT. Mycobiome Supporting Diet (MSD) proposed in this study is designed to restructure the gut microbiome (both bacterial and fungal communities) and support optimal GI tract health. It combines elements from several diets (e.g., Paleo, low-carbohydrate, vegetarian, and Mediterranean) and excludes elements of these diets that have been specifically proven to increase pathogenic fungi in the human gut. Our group examined application of MSD among healthy volunteers between the ages of 30 and 70 who agreed to follow the MSD for 28 days on a prospective trial. At the end of the study period, subjects had a 1.7-fold decrease in the abundance of Proteobacteria (considered a red flag for inflammation), with levels reduced from 38.6% to 23.3% with significantly increased of beneficial species such as Faeclibacterium prausnitzii (up 35.8%) , Bifidobacterium adolescentis (up 61.6%) , Roseburia (up 57.5%) , Lactobacillus (up 77.6%) , and Bacteroides. Furthermore, Pathogenic bacteria decreased significantly, including Escherichia coli (down 74%), Bacteroides fragilis (down 45.3%), and Clostridium (down 55.7%). After the study, all participants with GI symptoms reported moderate or dramatic improvements. Two thirds of the participants who chose to track their weight lost significant weight (between two and 10 pounds) over the testing period. Thirty percent of the participants reported moderate or dramatically improved fatigue and higher energy levels. Given the association between baseline gut dysbiosis and post-transplant GI toxicities and availability of a highly curated diet to optimize the richness and diversity of gut microbiome communities, in this trial (ClinicalTrials.gov Identifier: NCT04685525) we sought to examine the feasibility of MSD diet among MM patients undergoing transplant by assessing its potential effect on decreasing post-transplant GI toxicities. Methods: The primary objective of this study is to evaluate the feasibility of MSD diet using patient's adherence to the MSD diet. The adherence will be assessed 3 times before transplant on days -21, -14 and -7. The MSD diet will deem feasible if at least 80% of patients showed adherence defined by 2 out of 3 assessment marked "more than half a time". With sample size of 40 we will be able to estimate the adherence rate of 80% with 95% confidence interval of +/- 12%. To assess impact of MSD on micro- and mycobiome, a custom pipeline based on Greengenes V13_8 and Unite database V7.2 will be designed for the taxonomic classification of 16SrRNA and ITS sequences, respectively. Downstream data analysis will be performed using Qiime software. Statistical analysis will be performed using the statistical programming language R (version 3.3.0). Change across time in phyla and genus abundance at the community level will be assessed using the non-parametric multivariate distance-based analysis of variance using BC distance for dissimilarity metric along with its standardized binary form. Diversity will be analyzed in an unbiased manner using the Shannon diversity index, a measure of abundance taking into account microbial distribution. Richness will be also assessed, reflecting the microbial counts of the bacterial and fungal communities in each sample. Longitudinal analysis will be performed using all pair wise Multiple Comparison of Mean Ranks as implemented in the PMCMR plus R package version 1.2.0, employing Kruskal & Wallis test followed by Bonferroni-Dunn post-hoc adjustment. P <.05 will be considered statistically significant for all tests after correcting for multiple comparisons. Correction for multiple testing were performed using Benjamini-Hochberg adjustment method for multiple testing. Figure 1 Figure 1. Disclosures Malek: Sanofi: Other: Advisory Board; Bluespark Inc.: Research Funding; Amgen: Honoraria; Cumberland Inc.: Research Funding; Medpacto Inc.: Research Funding; Janssen: Other: Advisory board ; BMS: Honoraria, Research Funding; Takeda: Honoraria. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau.

A gap-filling algorithm for prediction of metabolic interactions in microbial communities

The study of microbial communities and their interactions has attracted the interest of the scientific community, because of their potential for applications in biotechnology, ecology and medicine. The complexity of interspecies interactions, which are key for the macroscopic behavior of microbial communities, cannot be studied easily experimentally. For this reason, the modeling of microbial communities has begun to leverage the knowledge of established constraint-based methods, which have long been used for studying and analyzing the microbial metabolism of individual species based on genome-scale metabolic reconstructions of microorganisms. A main problem of genome-scale metabolic reconstructions is that they usually contain metabolic gaps due to genome misannotations and unknown enzyme functions. This problem is traditionally solved by using gap-filling algorithms that add biochemical reactions from external databases to the metabolic reconstruction, in order to restore model growth. However, gap-filling algorithms could evolve by taking into account metabolic interactions among species that coexist in microbial communities. In this work, a gap-filling method that resolves metabolic gaps at the community level was developed. The efficacy of the algorithm was tested by analyzing its ability to resolve metabolic gaps on a synthetic community of auxotrophic Escherichia coli strains. Subsequently, the algorithm was applied to resolve metabolic gaps and predict metabolic interactions in a community of Bifidobacterium adolescentis and Faecalibacterium prausnitzii, two species present in the human gut microbiota, and in an experimentally studied community of Dehalobacter and Bacteroidales species of the ACT-3 community. The community gap-filling method can facilitate the improvement of metabolic models and the identification of metabolic interactions that are difficult to identify experimentally in microbial communities.